Evaluation of Lenvatinib, Pembrolizumab, and Chemotherapy in Advanced/Metastatic Gastroesophageal Adenocarcinoma: A Phase 3 Randomized Study

The primary objective of this Phase 3, randomized study is to evaluate the **safety** and **tolerability** of treatment with lenvatinib plus pembrolizumab plus chemotherapy in participants with advanced/metastatic gastroesophageal adenocarcinoma. Additionally, the study aims to compare the overall survival and progression-free survival between treatment groups. These objectives are clinically relevant as they assess the potential of the combination therapy to improve patient outcomes in a challenging cancer type, providing insights into its efficacy and safety profile.

Secondary objectives include:

• Comparing the overall response rate (ORR) between treatment groups.
• Estimating the duration of response (DOR) per RECIST 1.1 as assessed by blinded independent central review (BICR) for each treatment group in participants with a programmed cell death ligand 1 combined positive score ≥1 and in all participants.
• Evaluating the safety and tolerability of lenvatinib plus pembrolizumab plus chemotherapy versus chemotherapy alone.

The clinical trial involves a total of **659 participants** diagnosed with **advanced/metastatic gastroesophageal adenocarcinoma**. The study population includes both male and female subjects, with an age range that encompasses adults and older adults. Participants were selected based on specific criteria, including a confirmed diagnosis of previously untreated, locally advanced unresectable or metastatic gastroesophageal adenocarcinoma, and a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. The trial includes individuals with adequately controlled blood pressure and adequate organ function. Both male and female participants are required to adhere to specific reproductive health guidelines during the study. The trial population is characterized by a diverse range of health statuses, and the inclusion of a vulnerable population is noted. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy and safety of a combination therapy involving **lenvatinib**, **pembrolizumab**, and chemotherapy in participants with advanced or metastatic gastroesophageal adenocarcinoma. The trial is structured in two parts, with the primary objectives being the assessment of safety and tolerability in Part 1, and the comparison of overall survival and progression-free survival between treatment groups in Part 2. The trial is expected to last until February 2026, with participant recruitment having commenced in June 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of gastroesophageal adenocarcinoma, measurable disease, and adequate organ function. Following the screening, participants will be randomized to receive either the investigational treatment or standard care. The investigational treatment includes **oral** administration of lenvatinib and **intravenous infusion** of pembrolizumab, alongside chemotherapy agents such as **capecitabine**, **fluorouracil**, **oxaliplatin**, and **calcium folinate**. The maximum treatment period for most agents is 12 months, except for pembrolizumab, which extends up to 108 weeks.

Study visits will be scheduled regularly to monitor participants' health, assess treatment efficacy, and record any adverse events. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted. Participants are expected to remain in the study for the full duration unless conditions such as significant adverse events or disease progression necessitate early termination. The trial's endpoints include the number of participants with dose-limiting toxicities, adverse events, and those who discontinue due to adverse events, as well as overall survival and progression-free survival metrics.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Capecitabine** is provided as a film-coated tablet, administered orally. The maximum daily dose is 1000 mg/m², with a total maximum dose of 112,000 mg/m² over a treatment period of up to 12 months. This medication is a chemical compound used in the study.

**Lenvatinib** is administered in capsule form, also taken orally. The maximum daily dose is 20 mg, with a total maximum dose of 14,112 mg over a 12-month period. Lenvatinib is a chemical compound and is identified by the sponsor product code MK-7902.

**Fluorouracil** is provided as a solution for injection, administered via intravenous infusion. The maximum daily dose is 2800 mg/m², with a total maximum dose of 16,800 mg/m² over a 12-month period. This medication is a chemical compound used in the trial.

**Calcium Folinate Pentahydrate** is administered as a solution for injection via intravenous infusion. The maximum daily dose is 400 mg/m², with a total maximum dose of 2400 mg/m² over a 12-month period. This chemical compound is used to support the treatment regimen.

**Oxaliplatin** is provided as a concentrate for solution for infusion, administered intravenously. The maximum daily dose is 130 mg/m², with a total maximum dose of 520 mg/m² over a 12-month period. This chemical compound is part of the chemotherapy regimen in the study.

**Pembrolizumab**, marketed as Keytruda, is administered as a concentrate for solution for infusion via intravenous infusion. The maximum daily dose is 400 mg, with a total maximum dose of 7200 mg over a treatment period of up to 108 months. Pembrolizumab is a biological compound and is identified by the sponsor product code MK-3475.

**Calcium Levofolinate** is administered as a solution for injection via intravenous infusion. The maximum daily dose is 400 mg/m², with a total maximum dose of 2400 mg/m² over a 12-month period. This chemical compound is used in the study to enhance the efficacy of the chemotherapy regimen.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The study aims to evaluate the efficacy and safety of these medications in combination as a first-line intervention for advanced/metastatic gastroesophageal adenocarcinoma.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of **Overall Survival (OS)** and **Progression-Free Survival (PFS)** in participants with advanced/metastatic gastroesophageal adenocarcinoma. These will be measured in two parts: Part 1 will focus on the number of participants with dose-limiting toxicities, adverse events, and those who discontinued treatment due to adverse events. Part 2 will assess OS and PFS in participants with a Programmed Cell Death Ligand 1 (PD-L1) Combined Positive Score (CPS) ≥1, as well as in all participants, using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as assessed by Blinded Independent Central Review (BICR).

Secondary endpoints will include the **Objective Response Rate (ORR)** and **Duration of Response (DOR)**, both evaluated per RECIST 1.1 by BICR in participants with PD-L1 CPS ≥1 and in all participants. Additionally, the number of participants experiencing adverse events and those who discontinued treatment due to adverse events will be recorded. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to ensure comprehensive assessment of the treatment's impact on the disease.